Aza and oxo Diels–Alder reactions using cis-cyclohexadienediols of microbial origin: chemoenzymatic preparation of synthetically valuable heterocyclic scaffolds

Aza and oxo Diels–Alder reactions using enantiopure cis-cyclohexadienediols were studied. These dienediols were obtained from the biotransformation of monosubstituted arenes using bacterial dioxygenases (toluene and benzoate dioxygenases). Ethyl glyoxylate and its N-tosyl imine were used as dienophiles to afford the corresponding hetero Diels–Alder bicyclic adducts with excellent regio- and stereoselectivities. Quantum chemical calculations at the B3LYP/6-31+G(d,p) level of theory were performed to rationalize the observed selectivities especially the stereochemical aspects of the cycloadditions. The synthetic importance of these adducts is highlighted for the preparation of enantiopure 2,2,3,4,5,6-hexasubstituted piperidine and tetrahydropyran from toluene.

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(1S,3S,4R,7S,8S)-Ethyl-7,8-isopropylidenedioxy-1-methyl-2-oxabicycle[2.2.2]-5-octen-3-carboxylateC14H20O5[α]D21 = −51 (c 0.9, MeOH)Source of chirality: (1S,2R)-3-methylcyclohexa-3,5-diene-1,2-diolAbsolute configuration: (1S,3S,4R,7S,8S)

(1S,3S,4R,7S,8S)-Ethyl-7,8-isopropylidenedioxy-1-propil-2-oxabicycle[2.2.2]-5-octen-3-carboxylateC16H24O5[α]D21 = −7.4 (c 1.1, MeOH)Source of chirality: (1S,2R)-3-propylcyclohexa-3,5-diene-1,2-diolAbsolute configuration: (1S,3S,4R,7S,8S)

(1S,3S,4R,7S,8S)-Ethyl-7,8-isopropylidenedioxy-1-(acetoxymethyl)-2-oxabicyclo[2.2.2]-5-octen-3-carboxylateC16H22O7[α]D21 = −23.6 (c 1.2, MeOH)Source of chirality: (1S,2R)-3-(acetoxymethyl)cyclohexa-3,5-diene-1,2-diolAbsolute configuration: (1S,3S,4R,7S,8S)

(1S,3S,4S,7R,8S)-3-Ethyl-8-methyl-7,8-isopropylidenedioxy-2-oxabicycle[2.2.2]5-octene-3,8-dicarboxylateC15H20O7[α]D21 = +162 (c 0.5, MeOH)Source of chirality: (1S,2R)-1,2-dihydroxycyclohexa-3,5-diene -1-carboxylic acidAbsolute configuration: (1S,3S,4S,7R,8S)

(2R,3R,4S,5R,6S)-Ethyl-4,5-dihydroxy-3,6-bis(hydroxymethyl)-6-methyl-1-tosylpiperidine-2-carboxylateC21H31NO8S[α]D21 = +17.1 (c 0.76, MeCN)Source of chirality: (1S,2R)-3-methylcyclohexa-3,5-diene-1,2-diolAbsolute configuration: (2R,3R,4S,5R,6S)

(2S,3S,4S,5R,6S)-2,5,6-Tris(hydroxymethyl)-3,4-isopopilidenedioxy-2-methyltetrahydro-2H-pyran-3,4-diolC12H22O6[α]D21 = −45.7 (c 0.8, MeOH)Source of chirality: (1S,2R)-3-methylcyclohexa-3,5-diene-1,2-diolAbsolute configuration: (2S,3S,4S,5R,6S)